ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.917C>T (p.Ala306Val)

dbSNP: rs796052678
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187971 SCV000241574 likely pathogenic not provided 2016-08-01 criteria provided, single submitter clinical testing An A306V variant that is likely pathogenic has been identified in the KCNQ3 gene. The A306V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D305G, W309R, G310V) have been reported in the Human Gene Mutation Database in association with KCNQ3-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the A306V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001852468 SCV002190716 pathogenic Benign neonatal seizures 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 306 of the KCNQ3 protein (p.Ala306Val). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ3 protein function. ClinVar contains an entry for this variant (Variation ID: 205966). This missense change has been observed in individual(s) with clinical features of KCNQ3-related conditions (PMID: 29655203; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).

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